Structural Dynamics of Amyloid-β Protofibrils and Actions of Anti- Amyloid-β Antibodies as Observed by High-Speed Atomic Force Microscopy

Amyloid-fl (Afl) aggregation intermediates, including oligomers and protofibrils (PFs), have attracted attention as neurotoxic aggregates in Alzheimer's disease. However, due to the complexity of the aggregation pathway, the structural dynamics of aggregation intermediates and how drugs act on them have not been clarified. Here we used high-speed atomic force microscopy to observe the structural dynamics of Afl42 PF at the single-molecule level and the effect of lecanemab, an anti-Afl PF antibody with the positive results from Phase 3 Clarity AD. PF was found to be a curved nodal structure with stable binding angle between individual nodes. PF was also a dynamic structure that associates with other PF molecules and undergoes intramolecular cleavage. Lecanemab remained stable in binding to PFs and to globular oligomers, inhibiting the formation of large aggregates. These results provide direct evidence for a mechanism by which antibody drugs interfere with the Afl aggregation process.

Automated summary

This study used high-speed atomic force microscopy to observe the structural dynamics of Afl42 PF at the single-molecule level and the effect of lecanemab, an anti-Afl PF antibody. It was found that PF had a curved nodal structure and underwent intramolecular cleavage. Lecanemab remained stable in binding to PFs and globular oligomers, inhibiting the formation of large aggregates. These results provide direct evidence for the mechanism by which antibody drugs interfere with the Afl aggregation process.